The human IL-2 receptor and related cytokine receptor systems are being studied to clarify the T cell immune response in normal, neoplastic, and immunodeficient states. Following T-cell activation by antigen, the magnitude and duration of the T-cell immune response is determined by the amount of IL-2 produced, levels of receptors expressed, and time course of each event. The IL-2 receptor contains three chains, IL-2Ra, IL-2Rb, and gc. Dr. Leonard cloned IL-2Ra in 1984, his group discovered IL-2Rb in 1986, and reported in 1993 that mutation of the gc chain results in X-linked severe combined immunodeficiency (XSCID, which has a T-B+NK- phenotype) in humans. This group reported in 1995 that mutations of the gc-associated kinase, Jak3, result in an autosomal recessive form of SCID indistinguishable from XSCID and in 1998 that T-B+NK+ SCID results from mutations in the IL7R gene. Based on work in this lab and others, gc was previously shown to be shared by the receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. The group also previously characterized genes that were induced or repressed by IL-2, IL-4, IL-7, and IL-15, including showing the negative regulation of the IL-7 receptor alpha chain, a finding with implications in understanding how IL-2 can promote cell death, and the positive regulation of a dual specificity phosphatase, DUSP5, that negatively regulates IL-2-mediated activation of ERK kinases. The group has also extended its work on mechanisms of signaling by these cytokines. In prior work, the group also had identified and studied thymic stromal lymphopoeitin (TSLP), whose binding protein, TSPLR is most related to gc, and showed that although both TSLP and IL-7 share the IL-7 receptor alpha chain, the function of TSLP and IL-7 are distinctive, that mouse TSLP plays a distinctive role in CD4 T cell development whereas IL-7 and IL-15, which also share gc, favor CD8 T cell development, and that TSLP plays a critical role in the develop of asthma in a mouse model system. In the current year, the lab has extended studies related to genes regulated by gc dependent cytokines and further analyzed the actions of TSLP.[unreadable] [unreadable] Having previously published the cloning of the IL-21 receptor and creating IL-21 transgenic mice and IL-21R knockout mice and showing that IL-21 critically regulates immunoglobulin production as well as inducing B cell apoptosis, the group reported in the past year that IL-21 can also expand hematopoietic progenitor cells. In addition, the group substantially clarified the basis for IL-21 signaling by publishing a detailed mutagenesis of the IL-21R cytoplasmic domain, thus revealing the basis for IL-21-mediated activation of Stat1, Stat3, and Stat5. The group identified a critical role for a single tyrosine for proliferation and survival, and clarified that other pathways, including Ras/MAP kinase and PI 3-kinase/Akt, are also important for IL-21 signaling.[unreadable] [unreadable] The group also reported the critical role played by IL-21 in the differentiation of Th17 cells, cells that play an important role in many pathogenic processes, including Crohn's disease and psoriasis. Having previously provided data suggesting that IL-21 may contribute to the pathogenesis of a murine model of systemic lupus erythematosis, the group has extended its investigation in this area in work intended to more definitively establish a relationship of IL-21 to autoimmune disease in general and SLE in particular.[unreadable] [unreadable] Regarding TSLP, the group made a major contribution by reporting that contrary to the literature, both human and mouse TSLP exert major actions directly on CD4+ T cells, whereas previously it was reported that human TSLP did not act on these cells.[unreadable] [unreadable] Previously, it was shown that Stat5a and Stat5b are oncogenic; when overexpressed, these proteins led to the development of lymphoblasic lymphoma. In the past year it was found that this is not dependent on TCR stimulation. Moreover, in a collaborative study, it was reported that Stat5b activation can enhance hepatocellular carcinoma agrgressiveness through induction of epithelial-mesenchymal transition.[unreadable] [unreadable] Overall, these studies help to improve our understanding of signaling by gc family cytokines and TSLP. These findings clarify molecular mechanisms that are relevant to immunodeficiency, allergy, autoimmunity, and cancer, as well as to the basic control of T-cell and B-cell actions.